The DOI matches its Crossref record; 45 of the 47 references it cites were found in a registry or an index.
Yes-Associated Protein Up-regulates Jagged-1 and Activates the NOTCH Pathway in Human Hepatocellular Carcinoma
Open accessAbstract
Background & aims Cancer cells often lose contact inhibition to undergo anchorage-independent proliferation and become resistant to apoptosis by inactivating the Hippo signaling pathway, resulting in activation of the transcriptional co-activator yes-associated protein (YAP). However, the oncogenic mechanisms of YAP activity are unclear.Methods By using cross-species analysis of expression data, the Notch ligand Jagged-1 (Jag-1) was identified as a downstream target of YAP in hepatocytes and hepatocellular carcinoma (HCC) cells. We analyzed the functions of YAP in HCC cells via overexpression and RNA silencing experiments. We used transgenic mice that overexpressed a constitutively activated form of YAP (YAP(S127A)), and measured protein levels in HCC, colorectal and pancreatic tumor samples from patients.Results Human HCC cell lines and mouse hepatocytes that overexpress YAP(S127A) up-regulated Jag-1, leading to activation of the Notch pathway and increased proliferation. Induction of Jag-1, activation of Notch, and cell proliferation required binding of YAP to its transcriptional partner TEA domain family member 4 (TEAD4); TEAD4 binding required the Mst1/2 but not β-catenin signaling. Levels of YAP correlated with Jag-1 expression and Notch signaling in human tumor samples and correlated with shorter survival times of patients with HCC or colorectal cancer.Conclusions The transcriptional regulator YAP up-regulates Jag-1 to activate Notch signaling in HCC cells and mouse hepatocytes. YAP-dependent activity of Jag-1 and Notch correlate in human HCC and colorectal tumor samples with patient survival times, suggesting the use of YAP and Notch inhibitors as therapeutics for gastrointestinal cancer. Transcript profiling: microarray information was deposited at the Gene Expression Omnibus database (http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?token=jxepvsumwosqkve&acc=GSE35004).
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“Despite the protective effects of IL-6, YAP-mediated Notch signaling activation contributed to tumor growth in human hepatocellular carcinoma and murine hepatocytes (Tschaharganeh et al., 2013”
From Targeting Interleukin-6 Signaling in Clinic (2019) · cites this paper as Tschaharganeh et al., 2013
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“Over the years, a number of inhibitors targeting YAP/TAZ-TEAD have been reported, including peptides such as super-TDU (173),437 and small molecules such as verteporfin (174) and MGH-CP1 (175).438–440”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [439]
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Cites
1 retracted
Wang, C., Qi, R., Li, N., Wang, Z., An, H., Zhang, Q., Yu, Y., & Cao, X. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.002105 · Cited by 90
RetractedZhao, B., Wei, X., Li, W., Udan, R. S., Yang, Q., Kim, J., Xie, J., Ikenoue, T., Yu, J., Li, L., et al. (2007) · Genes & Development · doi:10.1101/gad.1602907 · Cited by 3,092 · cited 6×
“Mst1), occurs in 50 to 70% of HCCs.(3,5,11) Also, functional studies have revealed oncogenic properties for nuclear YAP.”
InfluentialTEAD mediates YAP-dependent gene induction and growth control
Zhao, B., Ye, X., Yu, J., Li, L., Li, W., Li, S., Yu, J., Lin, J. D., Wang, C.-Y., Chinnaiyan, A. M., et al. (2008) · Genes & Development · doi:10.1101/gad.1664408 · Cited by 2,498 · cited 1×
“YAP regulates target gene transcription in tumor and non-malignantly transformed cells through interaction with different transcription factors including TEAD family members.(18) Our results demonstrate that YAP-dependent expression of Jag-1 strictly depends on the presence of TEAD4, while other known binding partners…”
Elucidation of a universal size-control mechanism in Drosophila and mammals
Dong, J., Feldmann, G., Huang, J., Wu, S., Zhang, N., Comerford, S. A., Gayyed, M. F., Anders, R. A., Maitra, A., & Pan, D. (2007) · Cell · doi:10.1016/j.cell.2007.07.019 · Cited by 2,370 · cited 9×
“To define the effector mechanisms mediating protumorigenic properties of YAP, expression profiles of human HuH-7 cells after YAP knockdown were compared with transcriptomic data of murine hepatocytes with inducible YAP expression (Figure 1A).(5) YAP-dependent expression of genes inversely regulated (including CTGF, CX…”
InfluentialLiu-Chittenden, Y., Huang, B., Shim, J. S., Chen, Q., Lee, S.-J., Anders, R. A., Liu, J. O., & Pan, D. (2012) · Genes & Development · doi:10.1101/gad.192856.112 · Cited by 1,452 · cited 1×
“Importantly, the increased luciferase activity of Jag-1 region 1 was inhibited in a dose-dependent manner when either YAP or TEAD4 plasmid transfection was paralleled by treatment with verteporfin, a drug, which disrupts the YAP-TEAD binding (Figure 4D).(19)”
The Hippo transducer TAZ confers cancer stem cell-related traits on breast cancer cells
Cordenonsi, M., Zanconato, F., Azzolin, L., Forcato, M., Rosato, A., Frasson, C., Inui, M., Montagner, M., Parenti, A. R., Poletti, A., et al. (2011) · Cell · doi:10.1016/j.cell.2011.09.048 · Cited by 1,381 · cited 1×
“Accumulating evidence supports the importance of the tumor-suppressive Hippo pathway and its mediator YAP in cancer.(1,3-7,12,23) Here, we demonstrate that overexpression of YAP exerts its tumor-supporting properties partly through TEAD4dependent Jag-1 expression and subsequent activation of the Notch pathway in gastr…”
YAP1 increases organ size and expands undifferentiated progenitor cells
Camargo, F. D., Gokhale, S., Johnnidis, J. B., Fu, D., Bell, G. W., Jaenisch, R., & Brummelkamp, T. R. (2007) · Current Biology · doi:10.1016/j.cub.2007.10.039 · Cited by 1,252 · cited 5×
“For this purpose, primary murine hepatocytes were isolated from 10 week old transgenic animals expressing YAP under negative control of the liver-specific LAP doxycycline transactivator domain.(8) Short-term administration of doxycycline and subsequent downregulation of YAP were followed by reduced expression of Jag-1…”
InfluentialThe Hippo pathway in organ size control, tissue regeneration and stem cell self-renewal
Zhao, B., Tumaneng, K., & Guan, K.-L. (2011) · Nature Cell Biology · doi:10.1038/ncb2303 · Cited by 1,205 · cited 1×
“Inactivation of the Hippo pathway leads to the nuclear translocation of YAP and subsequent interaction with several transcription factors including TEAD and SMAD family members, Runx2, or p73.(2)”
Identification and validation of oncogenes in liver cancer using an integrative oncogenomic approach
Zender, L., Spector, M. S., Xue, W., Flemming, P., Cordon-Cardo, C., Silke, J., Fan, S.-T., Luk, J. M., Wigler, M., Hannon, G. J., et al. (2006) · Cell · doi:10.1016/j.cell.2006.05.030 · Cited by 1,065 · cited 7×
“Although transcription factors are believed to be non- 21 druggable due to large and stable protein/DNA surface interactions, crystal structure analysis of the YAP/TEAD4 complex demonstrated that the proteins are connected mainly via two short helices, one in the C-terminal domain of TEAD4 and one in the N-terminal re…”
InfluentialClassification and prediction of survival in hepatocellular carcinoma by gene expression profiling
Lee, J., Chu, I., Heo, J., Calvisi, D. F., Sun, Z., Roskams, T., Durnez, A., Demetris, A. J., & Thorgeirsson, S. S. (2004) · Hepatology · doi:10.1002/hep.20375 · Cited by 942
Self-citation
Research works printed but not linked: 1
- Camargo, 2007, YAP1 increases organ size and expands undifferentiated progenitor cells, Curr Biol, 17, 2054, 10.1016/j.cub.2007.10.039 · DOI · Paper page
Cited by
Sorted by citations
The Biology of YAP/TAZ: Hippo Signaling and Beyond
Piccolo, S., Dupont, S., & Cordenonsi, M. (2014) · Physiological Reviews · doi:10.1152/physrev.00005.2014 · Cited by 1,873
Angiogenic signaling pathways and anti-angiogenic therapy for cancer
Liu, Z., Chen, H., Zheng, L., Sun, L., & Shi, L. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01460-1 · Cited by 1,486
Notch Signaling in Development, Tissue Homeostasis, and Disease
Siebel, C., & Lendahl, U. (2017) · Physiological Reviews · doi:10.1152/physrev.00005.2017 · Cited by 1,001
Targeting Interleukin-6 Signaling in Clinic
Kang, S., Tanaka, T., Narazaki, M., & Kishimoto, T. (2019) · Immunity · doi:10.1016/j.immuni.2019.03.026 · Cited by 904
Hippo Pathway Activity Influences Liver Cell Fate
Yimlamai, D., Christodoulou, C., Galli, G. G., Yanger, K., Pepe-Mooney, B., Gurung, B., Shrestha, K., Cahan, P., Stanger, B. Z., & Camargo, F. D. (2014) · Cell · doi:10.1016/j.cell.2014.03.060 · Cited by 857
Metadata
- Authors
- Tschaharganeh, D. F., Chen, X., Latzko, P., Malz, M., Gaida, M. M., Felix, K., Ladu, S., Singer, S., Pinna, F., Gretz, N., Sticht, C., Tomasi, M. L., Delogu, S., Evert, M., Fan, B., Ribback, S., Jiang, L., Brozzetti, S., Bergmann, F., Dombrowski, F., Schirmacher, P., Calvisi, D. F., & Breuhahn, K.
- Affiliations
- University Hospital Heidelberg (DE)
- University of California, San Francisco (US)
- University of Chieti-Pescara (IT)
- Medizinische Fakultät Mannheim (DE)
- University of Southern California (US)
- Universität Greifswald (DE)
- Sapienza University of Rome (IT)
- Corresponding author
- Breuhahn, Kai
- ORCID
- Venue
- Gastroenterology
- Publisher
- Elsevier BV
- Published
- 2013-06
- Volume
- 144
- Issue
- 7
- Pages
- 1530-1542.e12
- ISSN
- 0016-5085 (ISSN-L)
- PMC
- PMC3665638
- OpenAlex
- W2060323466
- Cited by
- 326
- References
- 47
- Citations by year
- 2026: 8 · 2025: 16 · 2024: 16 · 2023: 19 · 2022: 26 · 2021: 29 · 2020: 35 · 2019: 26 · 2018: 26 · 2017: 25 · 2016: 28 · 2015: 35 · 2014: 28 · 2013: 8
- FWCI
- 19.34
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Gastroenterology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
- Funders
- National Institutes of Health
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hippo pathway signaling and YAP/TAZ
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer-related molecular mechanisms research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- YAP, Jagged1, Notch signaling, hepatocellular carcinoma, TEAD4, MST1/2, Hippo signaling pathway, colorectal cancer, pancreatic cancer, cell proliferation, patient survival, transcriptional coactivator, therapeutic target
- MeSH terms
- Serrate-Jagged Proteins, Jagged-1 Protein, YAP-Signaling Proteins, TEA Domain Transcription Factors, Animals, Calcium-Binding Proteins, DNA-Binding Proteins, Carcinoma, Hepatocellular, Humans, Liver Neoplasms, Membrane Proteins, Muscle Proteins, Phosphoproteins, Transcription Factors, Up-Regulation, Gene Expression Regulation, Neoplastic, Cell Cycle Proteins, Hepatocytes, Intercellular Signaling Peptides and Proteins, Cell Line, Tumor, Adaptor Proteins, Signal Transducing, Cell Proliferation, Mice, Receptors, Notch
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